CN115417973B

CN115417973B - Antibacterial polyurethane material and preparation method and application thereof

Info

Publication number: CN115417973B
Application number: CN202211369424.6A
Authority: CN
Inventors: 卢智慧; 刘琦; 陈泽萍; 郭金山
Original assignee: Huangpu Institute of Materials
Current assignee: Huangpu Institute of Materials
Priority date: 2022-11-03
Filing date: 2022-11-03
Publication date: 2023-03-24
Anticipated expiration: 2042-11-03
Also published as: CN115417973A

Abstract

The application relates to a preparation method of an antibacterial polyurethane material, which comprises the following steps: providing a quaternary ammonium salt compound of formula I, R ₁ And R ₂ Each independently selected from: -CH ₃ 、‑CH ₂ CH ₃ Or- (CH) ₂ )n ₃ OH，R ₃ is-S (CH) ₂ )n ₄ H, X are halogen, n ₁ Any integer selected from 2~8, n ₂ Any integer selected from 3~8, n ₃ Any integer selected from 1~3, n ₄ Any integer selected from 0~5, willL‑Pre-polymerizing lysine diisocyanate, polyester polyol, micromolecular polyol and an organic solvent, adding the quaternary ammonium salt compound for reaction, adding a catalyst for reaction, and freeze-drying to obtain the polyurethane foam material. The application also relates to an antibacterial polyurethane material which has excellent biodegradability and biocompatibility and can be used for preparing antibacterial and/or bacteriostatic biomedical materials.

Description

Antibacterial polyurethane material and preparation method and application thereof

Technical Field

The application relates to the technical field of biomedical materials, in particular to an antibacterial polyurethane material and a preparation method and application thereof.

Background

Along with the continuous improvement of living standard of people, the medical science and technology level is also improved day by day, the development of antibacterial medical materials is also quicker, and the polyurethane material has excellent biocompatibility and adhesivity and plays an important role in medical biomaterials. Antibacterial polyurethane materials have been widely used in wound care as a medical adjuvant.

CN113956437A records a preparation method of an antibacterial polyurethane sponge with quercetin groups introduced into a main chain, and the preparation method is complex in preparation process, high in product hardness and low in applicability. CN108546321A describes a high-biocompatibility biodegradable bone filling material, which contains a large amount of carbamido and hydrogen bonds, has insufficient toughness and needs to be improved in antibacterial ability.

CN111909343A describes a preparation method of an elastic antibacterial material, modified polyester polyol, an antibacterial agent, polybasic isocyanate and the like are subjected to prepolymerization, then a chain extender capable of generating ROS response is introduced for chain extension, and gastrodin is introduced for end capping, so that the mechanical property and the deformation resistance of the material can be improved, and the polyurethane antibacterial material still has good physical and mechanical properties after chemical bonds are broken in the ROS response drug release process. But the preparation is complex, the preparation cost is high, and the industrial large-scale production is not facilitated.

Accordingly, there is a need for a simple method for preparing an antibacterial polyurethane material having a wide range of applications.

Disclosure of Invention

The first aspect of the application provides a preparation method of an antibacterial polyurethane material, raw materials are easy to obtain, the operation is simple, the prepared antibacterial material has strong biocompatibility, the degradable and degradable products are nontoxic, the antibacterial ability is strong, and the application range is wide.

A first aspect of the present application provides a method for preparing an antibacterial polyurethane material, comprising the steps of:

providing a quaternary ammonium salt compound, wherein the quaternary ammonium salt compound has a structure shown in a formula I:

；

wherein the content of the first and second substances,

R ₁ and R ₂ Each independently selected from: -CH ₃ 、-CH ₂ CH ₃ Or- (CH) ₂ )n ₃ OH，

R ₃ is-S (CH) ₂ )n ₄ H，

X is a halogen, and X is a halogen,

n ₁ any integer selected from 2~8,

n ₂ any integer selected from 3~8,

n ₃ any integer selected from 1~3,

n ₄ any integer selected from 0~5;

providing a prepolymer, wherein the prepolymer is prepared by the following preparation steps: under protective gas, willL-Mixing lysine diisocyanate, polyester polyol, micromolecular polyol and an organic solvent, and carrying out prepolymerization reaction;

adding the quaternary ammonium salt compound into the prepolymer for reaction to prepare a first material;

adding a catalyst into the first material to carry out a stepwise polymerization reaction to prepare a second material;

freeze-drying the second material to obtain a polyurethane antibacterial material;

the molecular weight of the polyester polyol is 300 to 2000;

the molecular weight of the small molecular weight polyol is 100 to 300.

In some embodiments of the present application, the method of making, theL-The molar weight ratio of the lysine diisocyanate to the polyester polyol to the small molecular polyol is 1:0.2 to 0.5:0.1 to 0.35;

the above-mentionedL-The molar ratio of the lysine diisocyanate to the quaternary ammonium salt compound to the organic solvent is 1:0.1 to 0.3:10 to 15.

In some embodiments of the present application, the preparation method wherein the polyester polyol comprises polycaprolactone diol, polycarbonate diol, polycaprolactone triol and poly (A)L-Lactide) glycol;

the micromolecular polyhydric alcohol comprises one or more of ethylene glycol, 1,4-butanediol, glycerol, pentaerythritol, xylitol, ethanolamine, triethanolamine, trimethylolpropane, diglycerol, mannitol, sorbitol and sorbitol ester.

In some embodiments of the present application, the preparation method includes one or more of the following technical features:

(A) The prepolymerization reaction conditions comprise: heating at 50-80 deg.c;

(B) In the step of adding the quaternary ammonium salt compound for reaction, the reaction conditions include: heating at 50-75 deg.c;

(C) In the step of adding the catalyst for reaction, the reaction conditions include: heating at 20-30 deg.c.

In some embodiments of the present application, in the preparation method, the catalyst comprises one or more of bismuth neodecanoate, bismuth isooctanoate, stannous octoate, and dibutyltin dilaurate.

In some embodiments of the present application, the preparation method further comprises the following steps of preparing the quaternary ammonium salt compound: the general formula of the structure is HO (CH) ₂ )n ₁ NR ₁ R ₂ The monomer A and the general structural formula of R ₃ (CH ₂ )n ₂ Mixing the monomer B of X, and carrying out an ionization reaction at 70-100 ℃.

In some embodiments of the present application, in the preparation method, the conditions of the ionization reaction include one or more of the following characteristics:

(a) The reaction time is 24 h-30 h;

(b) Absolute ethyl alcohol is used as a solvent;

(c) The molar ratio of the monomer A to the monomer B is 1:1.

In a second aspect, the present application provides an antimicrobial polyurethane material prepared according to the preparation method provided in the first aspect of the present application.

In some embodiments of the present application, the antibacterial polyurethane material has a porosity of 65% to 80% and a water absorption of 350% to 500%.

In a third aspect of the present application, there is provided a use of the antibacterial polyurethane material provided in the second aspect of the present application in preparing any one of the following medical materials:

internal compression hemostatic material, body surface compression hemostatic material, tissue cavity filling material, antioxidant stress material and antibacterial material.

The preparation method is simple to operate, the quaternary ammonium salt compound (with both ends being hydroxyl and thioether groups) and the prepolymer (prepared by reacting appropriate isocyanate, polyalcohol and organic solvent) are provided, the quaternary ammonium salt compound and the prepolymer are prepolymerized, then the catalyst is added for reaction, and the product is obtained by freeze drying. The preparation method has the advantages of easily available raw materials and low cost, and can be used for industrial production.

According to the preparation method, the prepolymer with appropriate modulus can be prepared by adjusting the molecular weight and the addition proportion of the raw material polyol, so that the strength of the polyurethane product is changed, the polyurethane product has appropriate mechanical strength, and the application is wider. The latter step of adding quaternary ammonium salt compound (the hydroxyl group and thioether at both ends retain the reaction activity), greatly improves the hydrophilicity of the material and provides excellent antibacterial ability, and the prepared antibacterial polyurethane material further improves the biocompatibility and antioxidant stress ability due to the existence of thioether groups.

The antibacterial polyurethane material can be quickly degraded, and degradation products are nontoxic and absorbable, so that inflammation is not caused. The antibacterial polyurethane material also has ROS responsiveness, has excellent biodegradability and biocompatibility, and can be used for preparing various medical materials such as tissue cavity fillers, antioxidant stress, internal/body surface compression hemostasis, antibacterial materials and the like.

Detailed Description

The present application is further illustrated below by reference to the following examples and embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes or modifications can be made by those skilled in the art after reading the teaching of the present application, and these equivalents also fall within the scope of the claims appended to the present application.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

Term(s)

Unless otherwise stated or contradicted, terms or phrases used herein have the following meanings:

as used herein, the term "and/or", "and/or" is selected to encompass any of two or more of the associated listed items, as well as any and all combinations of the associated listed items, including any and all combinations of any two of the associated listed items, any more of the associated listed items, or all combinations of all of the associated listed items. The terms "preferably", "better", and the like are used herein only to describe better embodiments or examples, and it should be understood that the scope of the present application is not limited by these terms.

In the present application, "further", "still further", "specifically" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of the present application.

In the present application, the terms "first", "second", "third", etc. in the terms "first", "second", "third", etc. are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor is it to be construed as implicitly indicating the importance or quantity of the technical feature indicated. Moreover, "first," "second," "third," etc. are used merely for purposes of non-exhaustive enumeration and description, and should not be construed as a closed limitation of quantity.

In the present application, the technical features described in the open manner include a closed technical solution including the listed features, and also include an open technical solution including the listed features.

In this application, where a range of values (i.e., a numerical range) is recited, unless otherwise stated, alternative distributions of values within the range are considered to be continuous, and include both the numerical endpoints of the range (i.e., the minimum and maximum values), and each numerical value between the numerical endpoints. Unless otherwise specified, when a numerical range refers to integers only within the numerical range, both endpoints of the numerical range are inclusive of the integers and each integer between the endpoints is inclusive of the integer. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, the ranges disclosed herein are to be understood to include any and all subranges subsumed therein.

The temperature parameter in the present application is not particularly limited, and is allowed to be a constant temperature treatment or to vary within a certain temperature range. It will be appreciated that the described thermostatic process allows the temperature to fluctuate within the accuracy of the instrument control. Fluctuations are allowed within a range such as ± 0.5 ℃, ± 0.4 ℃, ± 0.3 ℃, ± 0.2 ℃ and ± 0.1 ℃.

In the present application, the weight may be in units of mass known in the chemical industry, such as μ g, mg, g, kg, etc.

In the present application, the molecular weight is an average molecular weight unless otherwise specified, and further, refers to a weight average molecular weight unless otherwise specified.

In a first aspect of the present application, a preparation method of an antibacterial polyurethane material is provided, the method has the advantages of readily available raw materials and simple operation, and the prepared antibacterial polyurethane material has an excellent antibacterial effect, good biocompatibility, excellent mechanical properties, strong applicability and a wide application range.

The preparation method is simple to operate, and isocyanate compounds (A, B and C) are preparedL-Lysine diisocyanate), polyol (polyester polyol and micromolecular polyol) and an organic solvent are prepolymerized to prepare a prepolymer, a quaternary ammonium salt compound is added into the prepolymer for reaction, a catalyst is added for reaction, and finally freeze drying is carried out to obtain the polyurethane foam.

The traditional antibacterial polyurethane material usually introduces micromolecules with antibacterial performance on prepolymer or directly blends non-reactive antibacterial agents, but the traditional antibacterial polyurethane material is generally not degradable and absorbable, has higher cost and poor adaptability. Through a large number of experiments, the applicant finds that the quaternary ammonium salt compound with a special structure is introduced into the polyurethane, so that the polyurethane has a good antibacterial effect, and is low in raw material cost and easy to prepare. The applicant carries out a series of comparative experiments, and according to the experimental results, the reason that the quaternary ammonium salt compound belongs to the cationic surfactant is presumed to be that the quaternary ammonium salt compound has strong biological adaptability and broad-spectrum bactericidal activity, and the hydroxyl groups and the thioether groups at the two ends respectively retain the reaction activity of the quaternary ammonium salt compound, so that in the process of reacting with the prepolymer, due to the further addition of the cationic group, the hydrophilicity of the material is greatly improved, excellent antibacterial capacity is provided, and the biocompatibility and the antioxidant stress capacity of the prepared polyurethane material are further improved due to the existence of the thioether groups.

In some embodiments of the present application, the quaternary ammonium salt compound has a structure according to formula I:

；

wherein the content of the first and second substances,

R ₁ and R ₂ Each independently selected from: -CH ₃ 、-CH ₂ CH ₃ Or- (CH) ₂ )n ₃ OH；

R ₃ is-S (CH) ₂ )n ₄ H；

X is halogen;

n1 is selected from any integer between 2 and 8;

n2 is selected from any integer between 3 and 8;

n3 is selected from any integer between 1 and 3;

n4 is selected from any integer between 0 and 5.

In some embodiments, the method for preparing the antibacterial polyurethane material comprises the following steps:

providing a quaternary ammonium compound, wherein the quaternary ammonium compound has a structure shown in the formula I, and each group is defined as the above;

under protective gas, willL-Mixing lysine diisocyanate, polyester polyol, micromolecular polyol and organic solvent to perform prepolymerization reactionPreparing a prepolymer;

adding a quaternary ammonium salt compound into the prepolymer for reaction to prepare a first material;

adding a catalyst into the first material to react to prepare a second material;

and (4) freeze-drying the second material to obtain the polyurethane antibacterial material.

In some embodiments, the quaternary ammonium salt compound is prepared by a process comprising: the general formula of the structure is HO (CH) ₂ )n1NR ₁ R ₂ The monomer A and the general structural formula of R ₃ (CH ₂ ) Mixing the monomers B of n2X, and carrying out an ionization reaction at 70-100 ℃; wherein R is ₁ 、R ₂ 、R ₃ N1 and n2 are each as defined above.

In some embodiments, the time for the ionization reaction is 24 h-30 h.

In some embodiments, the ionization reaction is performed using absolute ethanol as a solvent.

In some embodiments, the molar ratio of monomer a to monomer B is 1:1.

In some embodiments, the polyester polyol is a homopolyester diol or a homopolyester triol. Further, it may be included that the polyester polyol is selected from the group consisting of polycaprolactone diols, polycarbonate diols, polycaprolactone triols, and poly(s) (ii)L-Lactide) glycol.

In some embodiments, the polyester polyol has a molecular weight of 300 to 2000.

In some embodiments, the small molecule polyol has 2~6 hydroxyl groups. Further, one or more of ethylene glycol, 1,4-butanediol, glycerol, pentaerythritol, xylitol, ethanolamine, triethanolamine, trimethylolpropane, diglycerol, mannitol, sorbitol, and sorbitol esters may be included.

In some embodiments, the organic solvent comprises one or more of N, N-dimethylformamide, dioxane, and methylene chloride.

In some embodiments of the present invention, the substrate is,L-lysine diisocyanate and polyThe molar weight ratio of the ester polyol to the small molecular polyol is 1:0.2 to 0.5:0.1 to 0.35. The strength of the final antibacterial polyurethane material can be changed by adjusting the molecular weight and the addition proportion of the polyester polyol. In the antibacterial polyurethane material, the ester group endows the material with the capability of rapid degradation, the degradation product is nontoxic and absorbable, and the degradation product of a hard segment (such as carbamate, urea bond, isocyanurate, allophanate and the like) contains lysine, is one of amino acids essential to human bodies, and has strong biocompatibility.

In some embodiments, the conditions of the prepolymerization reaction include: heating at 50-80 deg.c. Further, the reaction time may be 10 to 15h.

The porosity of the antibacterial polyurethane material prepared by the preparation method can be adjusted within a certain range according to actual requirements, the adjustable range can be +/-5%, and in some embodiments, according to different addition amounts of the organic solvent, the porosity of the antibacterial polyurethane material can be 65% -80%, and further can be 60% -75%. Further, the antibacterial polyurethane material also has strong water absorption (which can exceed 350%). In some embodiments, the water absorption is from 350% to 500%, and further can be from 300% to 450%.

In some embodiments of the present invention, the substrate is,L-the molar ratio of the lysine diisocyanate to the quaternary ammonium salt compound to the organic solvent is 1:0.1 to 0.3:10 to 15.

In some embodiments, in the step of adding a quaternary ammonium salt compound to carry out the reaction, the reaction conditions include: heating at 50-75 deg.C. Further, the reaction time may be 3 to 5h.

In some embodiments, the catalyst comprises one or more of bismuth neodecanoate, bismuth isooctanoate, stannous octoate, and dibutyltin dilaurate.

In some embodiments, in the step of adding a catalyst to perform the reaction, the reaction conditions include: reacting at 20-30 ℃. Further, the reaction time may be 1h to 2h.

In a second aspect of the present application, an antibacterial polyurethane material is provided, which has excellent antibacterial and/or bacteriostatic effects, suitable mechanical strength, good biocompatibility, and various applicable scenarios, and can be used, for example, as an antioxidant stress material, such as a material for hemostasis by compression in vivo and/or on body surface, a tissue cavity filling material, a medical liquid dressing, and the like.

In some embodiments, the antibacterial polyurethane material has a compressive strength of 7.5 to 10.0kpa, and may further have a compressive strength of 6.5 to 7.5kpa.

In some embodiments, the antimicrobial polyurethane material is broken in a PBS solution at 37 ℃ for a period of 4 to 7 days.

Reactive Oxygen Species (ROS) are chemically active oxygen-containing molecules, which are one of the products of cellular metabolism. Under physiological conditions, ROS levels are carefully regulated, and they act as messengers in normal cell signaling, cell cycle, gene expression, and homeostasis. One of the most important oxidants in acute and chronic wounds, in high concentration, can induce oxidative stress, aggravate inflammation, and cause subsequent damage to cellular macromolecules (such as nucleic acids, membrane lipids, and cellular proteins).

In some embodiments of the present application, the antimicrobial polyurethane material also has the ability to deplete endogenous ROS, reduce oxidative stress and enhance the conversion of macrophage phenotype, which can prevent wound inflammation.

In a third aspect of the present application, an antibacterial polyurethane material is provided, which has ROS responsiveness, excellent biodegradability and biocompatibility, and can be used for preparing one or more of the following medical materials: compression hemostasis material, tissue cavity stuffing, antioxidant stress material and bacteriostasis material.

Some specific examples are as follows.

Experimental parameters not described in the following specific examples are preferably referred to the guidelines given in the present application, and may be referred to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by the manufacturer.

The starting materials and reagents mentioned in the following specific examples can be commercially available or can be prepared by a person skilled in the art according to known means.

Raw materials:

polycaprolactone triol, product number PCL3057, shenzhen plastic chemical limited;

2-chloroethyl methyl sulfide, CAS No. 603-07-2, wuhanxin Wei chemical Co., ltd;

3-dimethylamino-1-propanol, product number D144401-100ML, sigma aldrich trade ltd;

L-lysine diisocyanate with CAS number 45172-15-4, xian Kangnuo chemical Co., ltd, and redistilling;

triethanolamine type I, zhengzhou Yaodi chemical products, inc.;

n-butyldiethanolamine, shanghai Michelin Biochemical technology, inc.;

(N, N-diethyl) -4-amino-1-butanol, merrel Chemicals, inc., shanghai;

3- [ ethyl (methyl) amino ] propan-1-ol, shenzhen Aituo chemical Limited Co;

2-chloroethyl Ether sulfide Cangzhou Enke medicine science and technology, inc.

Example 1

1.1. Preparation of quaternary ammonium salt compounds

Weighing 11.06 g (0.1 mol) 2-chloroethyl methyl sulfide and 10.32g (0.1 mol) 3-dimethylamino-1-propanol, adding into a clean and dry 250mL single-neck flask, adding 100mL absolute ethyl alcohol, reacting at 70 ℃ under condensing reflux conditions for 24h, distilling under reduced pressure to remove residual solvent, separating and extracting with deionized water, and freeze-drying under vacuum to obtain 19.33 g quaternary ammonium salt compound S1 (S1) (0.1 mol)

）。

1.2. Preparation of polyurethane antibacterial material

Under the protection of dry nitrogen, 22.63g ofL-Lysine diisocyanate (0.1 mol) was mixed with 22g polycaprolactone triol (dried and dehydrated, 0.04mol, mw = 550), 1.5 g triethanolamine (0.01 mol) and 0.92 g glycerol (0.01 mol), dissolved in 110 mL dioxane,then reacting at 60 ℃ for 12 h to obtain the prepolymer.

Adding 4.28 g quaternary ammonium salt compound S1 (0.02 mol) into the prepolymer to react 4h, cooling to room temperature, adding 0.1g of catalyst (stannous octoate) to continue to react 1h, monitoring-NCO group disappearance by an infrared detector, transferring the solution gel to vacuum freeze drying 48 h, and obtaining the polyurethane antibacterial material P1.

Example 2

2.1. Preparation of quaternary ammonium salt compounds

Weighing 12.46g (0.1 mol) of 2-chloroethyl ethyl sulfide and 10.32g (0.1 mol) of 3-dimethylamino-1-propanol, adding the mixture into a clean and dry 250mL single-neck flask, then adding 100mL of absolute ethyl alcohol, reacting for 24h at 70 ℃ under the condition of condensation reflux, distilling under reduced pressure to remove residual solvent, separating and extracting by using deionized water, and obtaining 22.31g of quaternary ammonium salt compound S2 (S2) through vacuum freeze drying

）。

2.2. Preparation of polyurethane antibacterial material

Under the protection of dry nitrogen, 22.63g ofL-Lysine diisocyanate (0.1 mol) was mixed with 14.8g of polycaprolactone triol (dried and dehydrated, 0.04mol, mw = 370), 1.5 g of triethanolamine g (0.01 mol) and 1.29g of glycerol (0.014 mol), dissolved in 220 mL dioxane, and reacted at 60 ℃ for 12 h to prepare a prepolymer.

Adding 2.28 g quaternary ammonium salt compound S2 (0.01 mol) into the prepolymer for reaction for 3 hours, cooling to room temperature, adding 0.1g of catalyst (stannous octoate) for continuing reaction for 1h, monitoring the disappearance of NCO groups through an infrared detector, transferring the solution gel to vacuum freeze drying 48 h, and then preparing the polyurethane antibacterial material P2.

Example 3

3.1. Preparation of quaternary ammonium salt compounds

12.46g (0.1 mol) of 2-chloroethylethyl sulfide and 13.12g (0.1 mol) of 3-diethylamino-1-propanol were weighed into a clean, dry 250mL single-neck flask, followed by 100mL of absolute ethanol and reaction at 85 ℃ under reflux condensationAfter 24 hours, the residual solvent is removed by reduced pressure distillation, then the mixture is separated and extracted by deionized water, and the product 23.30g of quaternary ammonium salt compound S3 (S) is obtained by vacuum freeze drying

）。

3.2. Preparation of polyurethane antibacterial material

Under the protection of dry nitrogen, 22.65 gL-Lysine diisocyanate (0.1 mol) and 40g polycaprolactone triol (dried and dehydrated, 0.02mol, mw = 2000), 4.48g triethanolamine (0.03 mol) and 0.63g ethylene glycol (0.01 mol) are mixed, dissolved in dioxane of 220 mL, and then reacted at 70 ℃ for 12 h to prepare a prepolymer.

Adding 7.67g of quaternary ammonium salt compound S3 (0.03 mol) into the prepolymer for reaction for 5 hours, cooling to room temperature, adding 0.1g of catalyst (bismuth neodecanoate) for continuing reaction for 1h, monitoring disappearance of NCO groups by an infrared detector, transferring the solution gel to vacuum freeze drying 48 h, and then preparing the polyurethane antibacterial material P3.

Example 4

4.1. Preparation of quaternary ammonium salt compounds

Weighing 12.46g (0.1 mol) of 2-chloroethyl ethyl sulfide and 13.12g (0.1 mol) of 3-diethylamino-1-propanol, adding the mixture into a clean and dry 250mL single-neck flask, then adding 100mL of absolute ethyl alcohol, reacting for 24h under the condition of 100 ℃ condensation reflux, distilling under reduced pressure to remove residual solvent, separating and extracting by using deionized water, and obtaining 23.30g of quaternary ammonium salt compound S3 (S) (through vacuum freeze drying)

）。

4.2. Preparation of polyurethane antibacterial material

Under the protection of dry nitrogen, 22.65 gL-Lysine diisocyanate (0.1 mol) was mixed with 35 g polycaprolactone triol (dried and dehydrated, 0.035mol, mw = 1000), 2.24g triethanolamine (0.015 mol) and 0.63g ethylene glycol (0.01 mol), dissolved in 220 mL dioxane, and reacted at 60 ℃ for 12 h to prepare a prepolymer.

Adding 16.82 g quaternary ammonium salt compound S4 (0.02 mol) into the prepolymer for reaction for 5 hours, cooling to room temperature, adding 0.1g of catalyst (bismuth neodecanoate) to continue reaction for 1h, monitoring disappearance of NCO groups through an infrared detector, transferring the solution gel to vacuum freeze drying 48 h, and then preparing the polyurethane antibacterial material P4.

Example 5

5.1. Preparation of quaternary ammonium salt compounds

Weighing 11.06 g (0.1 mol) 2-chloroethyl methyl sulfide and 11.72 g (0.1 mol) 3- [ ethyl (methyl) amino]Adding propane-1-alcohol into a clean and dry 250mL single-neck flask, then adding 100mL absolute ethyl alcohol, reacting 24h under the condition of 70 ℃ condensation reflux, distilling under reduced pressure to remove residual solvent, separating and extracting by using deionized water, and obtaining the product 18.23 g quaternary ammonium salt compound S4 (through vacuum freeze drying)

）。

5.2. Preparation of polyurethane antibacterial material

Under the protection of dry nitrogen, 22.63g ofL-Lysine diisocyanate (0.1 mol) is mixed with polycaprolactone triol (dried and dehydrated, 0.04mol, mw = 550) of 22g, triethanolamine (0.01 mol) of 1.5 g and glycerol (0.01 mol) of 0.92 g, dissolved in dioxane of 110 mL, and then reacted at 60 ℃ for 12 h to prepare a prepolymer.

Adding 4.28 g quaternary ammonium salt compound S4 (0.02 mol) into the prepolymer to react with 4h, cooling to room temperature, adding 0.1g of catalyst (stannous octoate) to continue reacting with 1h, monitoring by an infrared detector that NCO groups disappear, transferring the solution gel to vacuum freeze drying 48 h, and obtaining the polyurethane antibacterial material P5.

Example 6

6.1. Preparation of quaternary ammonium salt compounds

Weighing 11.06 g (0.1 mol) 2-chloroethyl methyl sulfide and 14.52 g (0.1 mol) (N, N-diethyl) -4-amino-1-butanol, adding into clean and dry 250mL single-neck flask, adding 100mL absolute ethyl alcohol, reacting 24h under 70 deg.C condensing reflux condition, evaporating under reduced pressureDistilling to remove residual solvent, separating and extracting with deionized water, and vacuum freeze drying to obtain product 18.93 g quaternary ammonium salt compound S5 (

）。

6.2. Preparation of polyurethane antibacterial material

Adding 4.28 g quaternary ammonium salt compound S5 (0.02 mol) into the prepolymer to react with 4h, cooling to room temperature, adding 0.1g of catalyst (stannous octoate) to continue reacting with 1h, monitoring by an infrared detector that NCO groups disappear, transferring the solution gel to vacuum freeze drying 48 h, and obtaining the polyurethane antibacterial material P6.

Example 7

7.1. Preparation of quaternary ammonium salt compounds

Weighing 11.06 g (0.1 mol) 2-chloroethyl methyl sulfide and 16.12g (0.1 mol) N-butyldiethanolamine, adding into a clean and dry 250mL single-neck flask, then adding 100mL anhydrous ethanol, reacting under the condition of 70 ℃ condensation reflux for 24h, carrying out vacuum distillation to remove residual solvent, then separating and extracting by using deionized water, and obtaining a product 19.73 g quaternary ammonium salt compound S6 through vacuum freeze drying

）。

7.2. Preparation of polyurethane antibacterial material

Adding 4.28 g quaternary ammonium salt compound S6 (0.02 mol) into the prepolymer to react with 4h, cooling to room temperature, adding 0.1g of catalyst (stannous octoate) to continue reacting with 1h, monitoring by an infrared detector that NCO groups disappear, transferring the solution gel to vacuum freeze drying 48 h, and obtaining the polyurethane antibacterial material P7.

Comparative example 1

A quaternary ammonium salt compound S1 was prepared by a preparation method substantially the same as that of example 1.

The polyurethane antibacterial material (polyurethane antibacterial material A1) is prepared by adopting the following preparation method: under the protection of dry nitrogen, 11.33 gL-Lysine diisocyanate (0.05 mol) was mixed with 25 g polycaprolactone triol (dried and dehydrated, 0.01mol, mw = 2500), 0.75g triethanolamine (0.005 mol) and 0.46g glycerol (0.005 mol), dissolved in 220 mL dioxane, and reacted at 60 ℃ for 20 h to prepare a prepolymer.

Adding 4.56 g quaternary ammonium salt compound S1 (0.02 mol) into the prepolymer for reaction for 3h, cooling to room temperature, adding 0.1g of catalyst (stannous octoate) for continuing reaction for 1h, monitoring disappearance of NCO groups through an infrared detector, and transferring the solution gel to vacuum freeze drying 48 h.

Comparative example 2

The polyurethane antibacterial material (polyurethane antibacterial material A2) is prepared by adopting the following preparation method:

under the protection of dry nitrogen, 11.33 gL-Lysine diisocyanate (0.05 mol) was mixed with 25 g polycaprolactone triol (dried and dehydrated, 0.01 mol), 0.75g triethanolamine (0.005 mol) and 0.46g glycerol (0.005 mol), 5.73g gastrodine (0.01 mol) was added for capping, dissolved in 220 mL dioxane, and reacted at 60 ℃ for 20 h.

Comparative example 3

A quaternary ammonium salt compound S3 was prepared by substantially the same preparation method as in example 4.

The polyurethane antibacterial material (polyurethane antibacterial material A3) is prepared by adopting the following preparation method: under the protection of dry nitrogen, 11.33 gL-Lysine diisocyanate (0.05 mol) and 22g of polycaprolactone tris (II)A prepolymer was prepared by mixing a polyol (dehydrated, dried, 0.04mol, mw = 550), 1.49g of triethanolamine (0.01 mol), 0.9g1, 4-butanediol (0.01 mol) and 0.46g of glycerol (0.005 mol), dissolving the mixture in 300 mL dioxane, and reacting the mixture at 60 ℃ for 12 h.

Adding 4.56 g quaternary ammonium salt compound S3 (0.02 mol) into the prepolymer for reaction for 5h, cooling to 10 ℃, adding 0.1g of catalyst (stannous octoate) to continue the reaction for 1h, monitoring the disappearance of NCO groups by an infrared detector, and transferring the solution gel to vacuum freeze drying 48 h.

Comparative example 4

A quaternary ammonium salt compound S4 was prepared by substantially the same preparation method as in example 5.

The polyurethane antibacterial material (polyurethane antibacterial material A4) is prepared by adopting the following preparation method: 22.63g under dry nitrogen blanketL-Lysine diisocyanate (0.1 mol) is mixed with polycaprolactone triol (dried and dehydrated, 0.04mol, mw = 550) of 22g, triethanolamine (0.01 mol) of 1.5 g and glycerol (0.01 mol) of 0.92 g, dissolved in dioxane of 110 mL, and then reacted at 35 ℃ for 12 h to prepare a prepolymer.

Adding 4.28 g quaternary ammonium salt compound S4 (0.02 mol) into the prepolymer to react with 3h, cooling to room temperature, adding 0.1g catalyst (stannous octoate) to continue reacting with 0.5 h, monitoring the disappearance of NCO groups through an infrared detector, and transferring the solution gel to vacuum freeze drying 30 h.

Performance testing

The polyamide antibacterial materials in the example 1~7 and the comparative example 1~4 are subjected to performance tests, and the test items and the methods are as follows:

(1) Porosity of sponge

The porosity was measured in parallel 3 times by mercury intrusion method and the average value was taken.

(2) Density of polyurethane sponge

The density of the sponge material is measured by adopting a polyurethane sponge foaming densimeter model KW-300Y of Xiamen King electronics Co., ltd, the Archimedes buoyancy method principle is adopted, and a specific gravity value of a sample is converted by using two variables of empty weight W1 and water weight W2 of the sample to be measured as reference according to multiple international measurement standards such as ASTM D297-93, D792-00, D618 and D891.

(3) Antibacterial property

The test mode is as follows: sponge samples were cut into 5mm × 5mm sections, sterilized by irradiation, and cultured in agar medium using overnight cultures obtained from single colonies of Escherichia coli, and each culture solution (1 mL) was inoculated into 9mL of PBS buffer solution to give a concentration of 3 × 10 ^-5 ×10 ⁵ Colony Forming units (CFUs/mL) at a concentration of 3X 10 ^-5 ×10 ⁵ The bacterial solutions of CFUs/mL were tested for bacteriostasis in 10cm diameter dishes.

(4) Compressive strength

The model of the polyurethane sponge universal tester adopting the limited public company of the testing instrument of the Jinan-Nuo century is UH4502, and the sample is taken to be 1 multiplied by 2cm ³ Before testing, the samples are dried in an oven at 40 ℃ for 4 hours to eliminate the influence of moisture on the mechanical properties of the samples.

(5) Degradation Properties

And (3) the degradation time of the sponge is determined by adding 50mL of physiological saline into a 100mL conical flask, cutting the sponge into blocks of 1.0cm multiplied by 1.0cm, keeping the temperature at 37 ℃ for a certain time, then slightly shaking the conical flask, and determining the degradation time of the sponge when the sponge is broken (the original shape is not kept), namely the mechanical property is lost.

(6) Water absorption rate

Drying the sample at 50 ℃, taking out the sample after reaching a constant weight, cooling the sample to room temperature, weighing the sample, circularly drying the sample until the weight difference theta is less than 0.02, considering that the sample is completely dried, and taking the final weight as the water absorption mass m1 of the sample. Putting the sample into a distilled water beaker, covering the sample with a wire mesh, ensuring that the sample is at least 50mm below the liquid level, removing bubbles on the surface of the sample, fully absorbing water, heating to boiling, keeping the temperature at 90 ℃, taking out the sample, putting the sample into a beaker at 23 ℃ for 1h, weighing the sample as m2, and obtaining the water absorption rate of r = (m 2m 1)/mL.

(7) Anti-inflammatory Activity

The anti-inflammatory activity of LPS-induced secretion of inflammatory factors (IL-6, IL-1. Beta., TNF-. Alpha.) and NO release from RAW264.7 macrophages was evaluated. Determining the content of NO in the supernatant of RAW264.7 cells of LPS-induced macrophages by a dosing group by utilizing a Griess method; ELISA method was used to test the effect of the administration group on the release of TNF-alpha and IL-6 from the supernatant of LPS-induced macrophage RAW 264.7. The test results are given in table 1 below.

TABLE 1 results of performance test of the polyamide antibacterial materials in example 1~7 and comparative example 1~4

	Porosity (%)	Density of	Diameter of bacteriostatic circle (mm)	Compressive strength (kpa)	Degradation time (d)	Water absorption (%)	Release of NO (μmol/mL)
								Example 1	79	32	30	7.20	4.5	397	2.65±0.23
Example 2	76	34	31	7.14	4.0	365	2.48±0.51
								Example 3	76	34	28	7.23	4.2	367	2.53±0.33
Example 4	77	35	33	7.10	4.3	375	2.45±0.42
								Example 5	78	33	30	7.10	4.1	370	2.46±0.43
Example 6	77	34	29	7.21	4.2	368	2.51±0.12
								Example 7	79	32	31	7.16	4.1	390	2.63±0.35
Comparative example 1	68	40	25	5.22	8.9	230	4.21±0.41
								Comparative example 2	65	42	28	4.32	8.3	263	5.06±0.45
Comparative example 3	67	39	22	5.75	8.6	270	5.21±0.61
								Comparative example 4	40	52	28	5.59	8.3	258	5.12±0.33

As can be seen from the above table, the larger the diameter of the inhibition zone is, the better the inhibition effect is, the smaller the release amount of NO is, the better the inhibition effect is, the data of examples 1 to 7 show that the thioether quaternary ammonium salt and polyurethane polymer has very strong antibacterial and anti-inflammatory properties, and has better antibacterial activity and effect compared with other antibacterial substances, high biocompatibility, certain toughness, usability and ROS responsiveness, the release of NO in the examples is less, which is obviously lower than that in the comparative examples, which indicates that the anti-inflammatory activity is better, and the thioether quaternary ammonium salt can be used in materials such as in vivo and/or body surface compression hemostatic materials, tissue cavity filling materials, medical liquid dressings, and the like.

All documents mentioned in this application are incorporated by reference into this application as if each were individually incorporated by reference. Citations referred to in this application are incorporated by reference in their entirety for all purposes unless otherwise conflicting with an application purpose and/or technical solution of the present application. Where a citation is referred to in this application, the definition of a feature, term, noun, phrase, or the like, in the citation is also incorporated by reference. In the case of citations in the present application, examples and preferred embodiments of the cited features of the related art are also incorporated by reference into the present application, but are not intended to limit the applicability of the present application. It should be understood that where the citation conflicts with the description herein, the application will control or be adapted in accordance with the description herein.

The technical features of the embodiments and examples described above can be combined in any suitable manner, and for the sake of brevity, all possible combinations of the technical features of the embodiments and examples described above are not described, but should be considered within the scope of the present disclosure as long as there is no contradiction between the combinations of the technical features.

The above-described examples merely represent several embodiments of the present application and are not to be construed as limiting the scope of the claims. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the concept of the present application, which falls within the scope of protection of the present application. Further, it should be understood that various changes or modifications can be made by those skilled in the art after reading the above teaching of the present application, and the obtained equivalent forms also fall within the protection scope of the present application. It should also be understood that technical solutions obtained by logical analysis, reasoning or limited experiments based on the technical solutions provided by the present application are all within the scope of the claims appended to the present application. Therefore, the protection scope of the present patent shall be subject to the appended claims, and the description can be used to interpret the contents of the claims.

Claims

1. The preparation method of the antibacterial polyurethane material is characterized by comprising the following steps:

wherein the content of the first and second substances,

R ₃ is-S (CH) ₂ )n ₄ CH ₃ ，

X is a halogen, and X is a halogen,

n ₁ any integer selected from 2~8,

n ₂ any integer selected from 3~8,

n ₃ any integer selected from 1~3,

n ₄ any integer selected from 0~4;

providing a prepolymer, wherein the prepolymer is prepared by the following preparation steps: under protective gas, willL-Mixing lysine diisocyanate, polyester polyol, micromolecular polyol and an organic solvent, and carrying out prepolymerization reaction; the prepolymerization reaction conditions comprise: heating at 50-80 deg.c;

the molecular weight of the polyester polyol is 300 g/mol-2000 g/mol;

the molecular weight of the micromolecular polyol is 100-300 g/mol;

wherein the molar weight ratio of the L-lysine diisocyanate, the polyester polyol and the small molecule polyol is 1:0.2 to 0.5:0.1 to 0.35;

the molar weight ratio of the L-lysine diisocyanate to the quaternary ammonium salt compound to the organic solvent is 1:0.1 to 0.3:10 to 15.

2. The process according to claim 1, wherein the prepolymerization is carried out for 10 to 15h.

3. The preparation method according to claim 1, wherein the polyester polyol comprises one or more of polycaprolactone diol, polycarbonate diol, polycaprolactone triol and poly (L-lactide) diol;

the small molecular polyol comprises one or more of pentaerythritol, xylitol, triethanolamine, trimethylolpropane, diglycerol, mannitol, sorbitol and esters thereof.

4. The preparation method according to claim 3, characterized by comprising one or more of the following technical characteristics:

5. The preparation method of claim 4, wherein the catalyst comprises one or more of bismuth neodecanoate, bismuth isooctanoate, stannous octoate and dibutyltin dilaurate.

6. The method of making any one of claims 1~5 further comprising the step of making the quaternary ammonium salt compound by: the general formula of the structure is HO (CH) ₂ )n ₁ NR ₁ R ₂ The monomer A and the general structural formula of R ₃ (CH ₂ )n ₂ Mixing the monomer B of X, and carrying out an ionization reaction at 70-100 ℃.

7. The method according to claim 6, wherein the conditions of the ionization reaction include one or more of the following characteristics:

(a) The reaction time is 24 h-30 h;

(b) Absolute ethyl alcohol is used as a solvent;

(c) The molar ratio of the monomer A to the monomer B is 1:1.

8. An antibacterial polyurethane material prepared according to the preparation method of any one of claims 1~7.

9. The antibacterial polyurethane material of claim 8, wherein the antibacterial polyurethane material has a porosity of 65% to 80% and a water absorption of 350% to 500%.

10. Use of the antibacterial polyurethane material of any one of claims 8~9 in the preparation of any one of the following medical materials: